Multiple diseases and conditions, including hypertension, coronary artery disease, congestive heart failure and chronic renal failure, are initiated or associated with endothelial dysfunction. The maintenance of balanced vascular pressure, patency and perfusion, the inhibition of thrombosis and induction of fibrinolysis characterise normal endothelial function. In contrast, interactions of numerous proinflammatory processes, reduced vasodilation and prothrombic properties distinguish endothelial dysfunction. It is also seen in type 1 and 2 diabetes and in the normotensive, normoglycaemic, first-degree relatives of patients with type 2 diabetes. Endothelial dysfunction has also been shown to occur in the metabolic syndrome, dyslipidaemia, insulin resistance, obesity, hyperhomocysteinemia, sedentary lifestyle and smoking.
The association of the inflammatory state with obesity and insulin resistance was described in 1993 by Hotamisligil et al. Additional studies have shown that obesity is a state of chronic inflammation significantly associated with increased plasma concentrations of C-reactive protein (CRP), interleukin-6 (IL6) and plasminogen-activator inhibitor-1 (PAI-1). Likewise, TNFα levels in obese patients correlate significantly with body mass index (BMI).
Tumor necrosis factor-(TNF-alpha) is an inflammatory cytokine1 that is expressed by macrophages and cardiac tissue early during the myocardial ischemia-reperfusion (I/R) injury. Elevations of TNF-expression also appear to cause cardiomyopathy. Interestingly, both cardiomyopathy and I/R injury are characterized by endothelial dysfunction, but, a putative role for TNF-alpha in the abnormal vasodilatory responses during I/R has not been elucidated.
Therapy of airway diseases associated with cough and inflammation, such as bronchial asthma and chronic obstructive pulmonary disease, several agents from a group of xanthine derivatives are historically used. Although they are generally considered to be non-selective inhibitors of PDE without selective action on its single isoforms, in therapeutically relevant plasma concentrations several other mechanisms are involved in their effects, e.g., antagonism with adenosine receptors, activation of histone-deacetylases, and others. Although bonchodilating and anti-inflammatory actions of PDE inhibitors have been elucidated, little is known about antitussive effects of xanthine derivatives or selective PDE inhibitors (PDE3, PDE4, PDE5).
Beyond the impairment of endothelium-dependent vasomotion, endothelial dysfunction promotes key aspects of the atherosclerotic disease process, ie, vascular inflammation and thrombosis that are relevant at all stages of the disease. Conversely, a systemic inflammatory response that may involve detrimental effects of C-reactive protein on the endothelium augments endothelial dysfunction. Accumulating evidence suggests profound prognostic implications of the degree of coronary and peripheral endothelial dysfunction, as assessed in response to acetylcholine or flow dependent dilation (FDD).
Managing acute pathology of often relies on the addressing underlying pathology and symptoms of the disease. There is currently a need in the art for new compositions to treatment or delay of the onset of Inflammatory Disorders and its associated complications progression.